Hearing loss and tinnitus: association studies for complex-hearing disorders in mouse and man.

Genome-wide association studies (GWAS) provide an unbiased first look at genetic loci involved in aging and noise-induced sensorineural hearing loss and tinnitus. The hearing phenotype, whether audiogram-based or self-report, is regressed against genotyped information at representative single nucleotide polymorphisms (SNPs) across the genome. Findings include the fact that both hearing loss and tinnitus are polygenic disorders, with up to thousands of genes, each of effect size of < 0.02. Smaller human GWAS' were able to use objective measures and identified a few loci; however, hundreds of thousands of participants have been required for the statistical power to identify significant variants, and GWAS is unable to assess rare variants with mean allele frequency < 1%. Animal studies are required as well because of inability to access the human cochlea. Mouse GWAS builds on linkage techniques and the known phenotypic differences in auditory function between inbred strains. With the advantage that the laboratory environment can be controlled for noise and aging, the Hybrid Mouse Diversity Panel (HDMP) combines 100 strains sequenced at high resolution. Lift-over regions between mice and humans have identified over 17,000 homologous genes. Since most significant SNPs are either intergenic or in introns, and binding sites between species are poorly preserved between species, expression quantitative trait locus information is required to bring humans and mice into agreement. Transcriptome-wide analysis studies (TWAS) can prioritize putative causal genes and tissues. Diverse species, each making a distinct contribution, carry a synergistic advantage in the quest for treatment and ultimate cure of sensorineural hearing difficulties.

Large-scale phenotyping of ABR P1-N1 amplitudes before and after exposure to noise in 69 strains of mice.

ABR wave I amplitude represents the synapse of auditory nerve fibers with the inner hair cell and is highly correlated with synapse counts. Cochlear synaptopathy, the loss of synaptic connections between inner hair cells and auditory nerve fibers, has been well-demonstrated in animal models of noise-induced hearing loss. The peak-to-peak wave I amplitude was determined at baseline and 2 weeks after noise exposure. We determined the ABR wave I amplitude at 80 dB SPL at the frequencies of 8, 12, 16, 24, and 32 kHz. A total of 69 strains (1-8 mice/strain) were analyzed. A statistically significant post-noise reduction in wave I amplitude was observed in all the tested frequencies (p < 0.00001). We identify distinct patterns of noise susceptibility and make this complete phenotypic dataset available for general use. This data establishes a new resource for the study of NIHL in mice and we hope this database will be a useful tool to expand the research in this field.

The Genetics of Variation of the Wave 1 Amplitude of the Mouse Auditory Brainstem Response.

This is the first genome-wide association study with the Hybrid Mouse Diversity Panel (HDMP) to define the genetic landscape of the variation in the suprathreshold wave 1 amplitude of the auditory brainstem response (ABR) both pre- and post-noise exposure. This measure is correlated with the density of the auditory neurons (AN) and/or the compliment of synaptic ribbons within the inner hair cells of the mouse cochlea. We analyzed suprathreshold ABR for 635 mice from 102 HMDP strains pre- and post-noise exposure (108 dB 10 kHz octave band noise exposure for 2 h) using auditory brainstem response (ABR) wave 1 suprathreshold amplitudes as part of a large survey (Myint et al., Hear Res 332:113-120, 2016). Genome-wide significance levels for pre- and post-exposure wave 1 amplitude across the HMDP were performed using FaST-LMM. Synaptic ribbon counts (Ctbp2 and mGluR2) were analyzed for the extreme strains within the HMDP. ABR wave 1 amplitude varied across all strains of the HMDP with differences ranging between 2.42 and 3.82-fold pre-exposure and between 2.43 and 7.5-fold post-exposure with several tone burst stimuli (4 kHz, 8 kHz, 12 kHz, 16 kHz, 24 kHz, and 32 kHz). Immunolabeling of paired synaptic ribbons and glutamate receptors of strains with the highest and lowest wave 1 values pre- and post-exposure revealed significant differences in functional synaptic ribbon counts. Genome-wide association analysis identified genome-wide significant threshold associations on chromosome 3 (24 kHz; JAX00105429; p < 1.12E-06) and chromosome 16 (16 kHz; JAX00424604; p < 9.02E-07) prior to noise exposure and significant associations on chromosomes 2 (32 kHz; JAX00497967; p < 3.68E-08) and 13 (8 kHz; JAX00049416; 1.07E-06) after noise exposure. In order to prioritize candidate genes, we generated cis-eQTLs from microarray profiling of RNA isolated from whole cochleae in 64 of the tested strains.This is the first report of a genome-wide association analysis, controlled for population structure, to explore the genetic landscape of suprathreshold wave 1 amplitude measurements of the mouse ABR. We have defined two genomic regions associated with wave 1 amplitude variation prior to noise exposure and an additional two associated with variation after noise exposure.

Cochlear FLAIR Signal Changes in Hearing Preservation Vestibular Schwannoma Surgery.

OBJECTIVE: Cochlear fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) signal intensity has been shown to be elevated in patients with vestibular schwannomas (VS). This study evaluated the preoperative and postoperative cochlear signal on FLAIR sequences in patients undergoing hearing preservation surgery. STUDY DESIGN: Retrospective chart review. SETTING: Tertiary referral center. PATIENTS: All patients undergoing middle cranial fossa or retrosigmoid craniotomy for VS at a single institution from September 2013 to January 2017 were screened.Hearing was graded according to the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) hearing classification. Inclusion criteria included preoperative AAO-HNS class A or B hearing and available preoperative and postoperative FLAIR sequences. MAIN OUTCOME MEASURE: Signal intensity of cochlear FLAIR signal was measured in the affected cochlea and normalized to the contralateral cochlea. Hearing preservation was defined as AAO-HNS class A or B postoperatively. RESULTS: Eighteen patients met all inclusion criteria, and 12/18 experienced hearing preservation. There was no difference in preoperative FLAIR ratio between hearing preserved and nonpreserved groups (2.02 vs 2.32, p = 0.52). Postoperatively, FLAIR ratio was lower in the hearing preserved group compared to the nonpreserved group (1.19 vs 1.87, p = 0.033). CONCLUSIONS: The current study is the first to examine postoperative cochlear FLAIR changes in VS patients undergoing hearing preservation surgery. In our study population, abnormal hyperintense FLAIR signal normalized in patients experiencing successful hearing preservation, while those who lost hearing maintained abnormal signal. Future studies may investigate the role of FLAIR in guiding optimal timing of operative intervention in VS patients.